ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1274A>G (p.Asn425Ser) (rs28362261)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000297926 SCV000358248 likely benign Hypobetalipoproteinemia 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000417326 SCV000358249 likely benign Familial hypercholesterolemia 3 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000417326 SCV000503511 uncertain significance Familial hypercholesterolemia 3 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / Software predictions: Benign
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000454567 SCV000539996 benign not specified 2016-03-29 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.7% (173/10272) African chromosomes
Invitae RCV000417326 SCV000555875 benign Familial hypercholesterolemia 3 2019-12-31 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000336569 SCV000599431 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Integrated Genetics/Laboratory Corporation of America RCV000454567 SCV000699985 benign not specified 2019-11-18 criteria provided, single submitter clinical testing Variant summary: PCSK9 c.1274A>G (p.Asn425Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 282818 control chromosomes, predominantly at a frequency of 0.016 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 171 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Additionally, association studies have shown that this variant is not associated with low or high cholesterol (Kotowski et al 2006). Co-occurrence with another pathogenic variant has been reported ((LDLR c.1257 C>G, Y419X) (Pisciotta_2006). In a functional study N425S was secreted normally, and had similar ability to reduce cell-surface LDLR as wild-type PCKSK9 (Fasano_2009). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (3x), likely benign (2x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV000454567 SCV000730631 likely benign not specified 2017-10-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000776105 SCV000910948 benign Familial hypercholesterolemia 2018-03-23 criteria provided, single submitter clinical testing
Mendelics RCV000336569 SCV001135295 benign Familial hypercholesterolemia 1 2019-05-28 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000336569 SCV000606702 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.